Bendamustine hydrochloride, 4-[5-[Bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl]butyric acid hydrochloride, of the formula (VI):
was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available there from 1971 to 1992, as the hydrochloride salt, under the trade name Cytostasan®. Since then, it has been marketed in Germany under the trade name Ribomustin®. Bendamustine hydrochloride for injection is available in the United States under the tradename Treanda®. Bendamustine hydrochloride is an alkylating agent that is approved for the treatment of non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocytic leukemia.
Bendamustine hydrochloride is a benzimidazole analog. While bendamustine has been demonstrated as efficacious, it is known to be unstable, especially in aqueous solutions, leading to the formation of non-bendamustine products (i.e. “degradation impurities”). This leads to technical difficulties in its preparation and administration. In light of its instability in aqueous solution, bendamustine is supplied as a lyophilized cake of bendamustine hydrochloride salt. US2006/159713, US 2006/128777 and WO2010/036702 disclose various impurities of bendamustine hydrochloride which are as follows:

Jena et al. were the first to disclose the synthesis of bendamustine hydrochloride in German (GDR) Patent No. 34727. Krueger et al., in German (GDR) Patent No. 159877, recite a method as summarized in scheme-1 for the synthesis of bendamustine hydrochloride comprising the reaction of the 4-[1-methyl-5-bis-(2-hydroxyethyl)-benzimidazolyl-2]butyric acid ethyl ester (4) (or the corresponding methyl, propyl or butyl ester) with thionyl chloride in chloroform at 0-5° C. to form 4-[1-methyl-5-bis-(2-chloroethyl)-benzimidazolyl-2]butyric acid ethyl ester (5). Excess thionyl chloride is destroyed by stirring the reaction mixture in aqueous HCl. Finally, chloroform is distilled off and stirred at 95° C. for 3 hours. The reaction mixture is partially concentrated and the residue is diluted with water and stirred up to crystallization. Further purification is done by recrystallization from water.

Ozegowski et al., in Zentralblatt fuer Pharmazie, Pharmakotherapie and Laboratoriumsdiagnostik 110 (10), 1013-1019 (1971) disclose a process for the preparation of bendamustine hydrochloride monohydrate. The Chinese journal “Chinese Journal of New Drugs”, 2007, No. 23, Vol. 16, 1960-61 and J. Prakt. Chem. 20, 178-186 (1963) disclose another method for the synthesis of bendamustine hydrochloride monohydrate starting from 2,4-dinitrochlorobenzene as summarized in scheme-2.

The crucial conversions are reaction of 1-methyl-2-(4′-ethyl butyrate)-5-amino]-1H-benzimidazole 6 with ethylene oxide in the presence of water, sodium acetate and acetic acid, by maintaining at 5° C. for 5 hours and overnight at 20° C. to give 4-{5-[bis-(2-hydroxy-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid ethyl ester (dihydroxy ester) 7 as a jelly mass, which on chlorination using thionyl chloride in chloroform and subsequent in situ hydrolysis with concentrated HCl gave bendamustine hydrochloride. The publications also disclose a process for the recrystallization of bendamustine hydrochloride from water and the product obtained is a monohydrate with a melting point of 148-151° C.
IP.com Journal 2009, 9(7B), 21 discloses another process as shown below for the preparation of ethyl-4-[5-[bis(2-hydroxyethyl)amino]-1-methylbenzimidazol-2-yl]butanoate (III) wherein ethyl-4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl) butanoate (II) is reacted with 2-haloethanol in the presence of an inorganic base selected from the group consisting potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.

The PCT application WO 2010/042568 assigned to Cephalon discloses the synthesis of bendamustine hydrochloride as summarized in scheme-3 starting from 2,4-dinitroaniline in six steps. The crucial step is reductive alkylation of II-a, using borane-tetrahydrofuran and chloroacetic acid at ambient temperature, producing compound of formula I-a. Acid mediated hydrolysis of I-a using concentrated hydrochloric acid at reflux produced bendamustine hydrochloride which has a purity of 99.1%. The above PCT application also discloses a method of purification of bendamustine hydrochloride by agitating bendamustine hydrochloride in a mixture of DMF and THF at 75° C. for about 30 minutes followed by cooling to ambient temperature and isolating the solid by filtration.

The PCT application WO 2011/079193 assigned to Dr. Reddy's Laboratories discloses the synthesis of bendamustine hydrochloride as summarized in scheme-4 starting from compound of formula (II). The crucial step is alkylation of compound of formula II with 2-haloethanol in the presence of an organic base to give a compound of formula (III), which on chlorination with a chlorinating agent affords a compound of formula (IV). Compound of formula (IV) on hydrolysis in acidic medium gives bendamustine hydrochloride. The PCT application further discloses purification of bendamustine hydrochloride using aqueous hydrochloric acid and acetonitrile.

Most of the prior art processes described above involve the use of ethylene oxide for the preparation of bendamustine hydrochloride, which is often not suitable for industrial scale processes due to difficulty in handling ethylene oxide, which is shipped as a refrigerated liquid.
Further, the known processes involve the use of strongly acidic conditions and high temperatures in hydrolyzing the ethyl ester of bendamustine and subsequent in situ formation of bendamustine hydrochloride, resulting in increased levels of various process-related impurities IMP.-A (RRT-0.46), IMP.-B (RRT-1.27) and IMP.-C(RRT-1.31), whose removal is quite difficult and which makes the process less economically viable.

International Application Publication No. WO 2009/120386 describes various solid forms of bendamustine hydrochloride designated as bendamustine hydrochloride Form 1, bendamustine hydrochloride Form 2, bendamustine hydrochloride Form 3, bendamustine hydrochloride Form 4, amorphous bendamustine hydrochloride and mixtures thereof, as well as processes for their preparation and lyophilized compositions comprising the solid forms. According to the disclosure, the monohydrate of bendamustine hydrochloride has been prepared previously. The monohydrate has a reported melting point of 152-156° C., which is similar to that of the observed melting point of bendamustine hydrochloride Form 2.
It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself, or during the preparation of the API. Impurities in bendamustine hydrochloride or any active pharmaceutical ingredient (API) are undesirable and might be harmful.
Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that any impurities are present in the lowest possible levels, even if structural determination is not possible.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the active pharmaceutical ingredient, the product is analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. Purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, is as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities are limited to less than 0.1 percent.
Generally, impurities are identified spectroscopically and by other physical methods, and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the “retention time” (“RT”). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use “relative retention time” (“RRT”) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Therefore, there remains a need for improved processes for preparing bendamustine hydrochloride, producing bendamustine hydrochloride in high yield and purity, and well-suited for use on an industrial scale. Despite the existence of various polymorphic forms of bendamustine hydrochloride, there exists a need for a simple process for the preparation of the stable form of bendamustine hydrochloride which is amenable to scale up and results in high yield and purity.